Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, 11451 Riyadh, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, 11451 Riyadh, Saudi Arabia.
Prog Neuropsychopharmacol Biol Psychiatry. 2024 Dec 20;135:111091. doi: 10.1016/j.pnpbp.2024.111091. Epub 2024 Jul 18.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is marked by impaired social interactions, and increased repetitive behaviors. There is evidence of genetic changes in ASD, and several of these altered genes are linked to the process of DNA repair. Therefore, individuals with ASD must have improved DNA repair efficiency to mitigate risks associated with ASD. Despite numerous milestones in ASD research, the disease remains incurable, with a high occurrence rate and substantial financial burdens. This motivates scientists to search for new drugs to manage the disease. Disruption of glucagon-like peptide-1 (GLP-1) signaling, a regulator in neuronal development and maintains homeostasis, has been associated with the pathogenesis and progression of several neurological disorders, such as ASD. Our study aimed to assess the impact of semaglutide, a new GLP-1 analog antidiabetic medication, on behavioral phenotypes and DNA repair efficiency in the BTBR autistic mouse model. Furthermore, we elucidated the underlying mechanism(s) responsible for the ameliorative effects of semaglutide against behavioral problems and DNA repair deficiency in BTBR mice. The current results demonstrate that repeated treatment with semaglutide efficiently decreased autism-like behaviors in BTBR mice without affecting motor performance. Semaglutide also mitigated spontaneous DNA damage and enhanced DNA repair efficiency in the BTBR mice as determined by comet assay. Moreover, administering semaglutide recovered oxidant-antioxidant balance in BTBR mice. Semaglutide restored the disrupted DNA damage/repair pathways in the BTBR mice by reducing Gadd45a expression and increasing Ogg1 and Xrcc1 expression at both the mRNA and protein levels. This suggests that semaglutide holds great potential as a novel therapeutic candidate for treating ASD traits.
自闭症谱系障碍（ASD）是一种复杂的神经发育障碍，其特征是社交互动受损和重复性行为增加。ASD 存在遗传变化的证据，其中一些改变的基因与 DNA 修复过程有关。因此，ASD 患者必须提高 DNA 修复效率，以降低与 ASD 相关的风险。尽管 ASD 研究取得了许多里程碑式的进展，但该疾病仍然无法治愈，其发病率高，经济负担重。这促使科学家寻找新的药物来治疗这种疾病。胰高血糖素样肽-1（GLP-1）信号的中断，作为神经元发育和维持内稳态的调节剂，与几种神经退行性疾病的发病机制和进展有关，如 ASD。我们的研究旨在评估新型 GLP-1 类似物抗糖尿病药物司美格鲁肽对 BTBR 自闭症小鼠模型行为表型和 DNA 修复效率的影响。此外，我们还阐明了司美格鲁肽改善 BTBR 小鼠行为问题和 DNA 修复缺陷的潜在机制。目前的结果表明，重复给予司美格鲁肽可有效降低 BTBR 小鼠的自闭症样行为，而不影响运动表现。司美格鲁肽还通过彗星试验减轻了 BTBR 小鼠的自发性 DNA 损伤，并提高了其 DNA 修复效率。此外，给予司美格鲁肽可恢复 BTBR 小鼠的氧化还原平衡。司美格鲁肽通过降低 Gadd45a 的表达和增加 Ogg1 和 Xrcc1 的表达（mRNA 和蛋白水平），恢复了 BTBR 小鼠中破坏的 DNA 损伤/修复途径。这表明司美格鲁肽作为一种治疗 ASD 特征的新型治疗候选药物具有巨大的潜力。
